1-42164649-C-A

Variant names:

• chr1-42164649-C-A
• rs201660564
• NM_033553.3:c.64G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_033553.3(GUCA2A):​c.64G>T​(p.Val22Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,394,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: GUCA2A NM_033553.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 1 publications found

Genes affected

GUCA2A (HGNC:4682): (guanylate cyclase activator 2A) Predicted to enable guanylate cyclase activator activity. Predicted to be involved in positive regulation of guanylate cyclase activity and signal transduction. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033553.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCA2A	NM_033553.3	MANE Select	c.64G>T	p.Val22Phe	missense	Exon 1 of 3	NP_291031.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCA2A	ENST00000357001.3	TSL:1 MANE Select	c.64G>T	p.Val22Phe	missense	Exon 1 of 3	ENSP00000349493.2	Q02747
	GUCA2A	ENST00000888051.1		c.64G>T	p.Val22Phe	missense	Exon 1 of 3	ENSP00000558110.1
	GUCA2A	ENST00000949218.1		c.64G>T	p.Val22Phe	missense	Exon 1 of 3	ENSP00000619277.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000641 AC: 1 AN: 156046 AF XY: 0.0000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1394328 Hom.: 0 Cov.: 29 AF XY: 0.00000436 AC XY: 3 AN XY: 688004

African (AFR) AF: 0.0000317 AC: 1 AN: 31532

American (AMR) AF: 0.0000280 AC: 1 AN: 35718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 35744

South Asian (SAS) AF: 0.00 AC: 0 AN: 79142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4888

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1075124

Other (OTH) AF: 0.00 AC: 0 AN: 57774

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.054	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		1.1
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.83		Gain of sheet (P = 0.1208)
MVP		0.36
MPC		0.0044
ClinPred		0.97	D
GERP RS		4.7
PromoterAI		0.0068	Neutral
Varity_R		0.66
gMVP		0.75
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201660564; hg19: chr1-42630320;